Although we have made significant advances in the treatment of mood disorders, studies such as the STAR*D and STEP-BD have made us increasingly aware of the limitations of the effectiveness of our current treatment strategies.1,2

Moreover, the fact that the currently existing antidepressant treatments require several weeks to produce a clinically meaningful improvement leads to high rates of discontinuation, extended hospital stays, prolonged suffering—and possibly even increased rates of suicidal behavior.

A series of studies completed over the past 12 years suggest that a novel class of drugs that directly target the glutamatergic neurotransmitter system may produce rapid and robust antidepressant effects in patients who had previously not responded to the standard monoaminergic antidepressant medications. Here I discuss the clinical studies that demonstrate the antidepressant effect of ketamine and other glutamatergic drugs, review the risks associated with some of these medications, and highlight the many still unanswered questions regarding the treatments. I also present information on several ongoing clinical trials in this area and encourage use of the NIH-sponsored registry of clinical trials, http://clinicaltrials.gov, when treatment options are being considered for patients with treatment-resistant mood disorders.

FIGURE 1 Glutamate receptors in the mammalian CNS

Glutamate

Glutamate is by far the most abundant and ubiquitous neurotransmitter in the mammalian CNS (Figure 1). Although it is known to serve as the major excitatory neurotransmitter in the brain, it was only recognized as a true neurotransmitter less than 30 years ago.3 Since that time, accumulated evidence has demonstrated glutamate’s central role in mediating nearly all forms of brain function, including cognition, perception, learning, and emotion. There is increasing evidence that disrupted glutamatergic signaling can contribute to the pathophysiology of a large variety of neuropsychiatric disorders. Preclinical studies are beginning to elucidate the connections between impaired function of glutamatergic synapses and stress-related conditions, such as mood disorders.4

The earliest evidence that a glutamatergic drug could have antidepressant effects was presented by George Crane5 in the late 1950s, long before the recognition of glutamate as a neurotransmitter. He noted the rapid antidepressant effects of cycloserine—now known to be a partial agonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor—when it was used to treat patients with tuberculosis. He specifically remarked on the rapid improvement of insomnia, anorexia, and tension in those patients.

Although he noted “cycloserine may become a valuable agent in psychopharmacological research considering the fact that its chemical structure and mode of action are different from those of most drugs with psychic effects,” there was little follow-up until the late 1980s, when Phil Skolnick’s laboratory at the NIH began to seriously examine the role of the NMDA receptor in the pathology of depression and as a target for antidepressant drug development.6 A series of studies throughout the 1990s further identified the critical role of NMDA receptors in eliciting stress-related behavioral deficits and in the generation of antidepressant-like effects in rodent models while postmortem studies in humans reported specific abnormalities in NMDA receptor function in the brains of depressed patients and suicide victims.7

Ketamine

In 2000, Berman and colleagues8 were the first to demonstrate the rapid onset of antidepressant effects with an NMDA receptor antagonist. In a small, placebo-controlled, proof-of-concept, crossover study of 7 patients, they found that a subanesthetic dose of ketamine (0.5 mg/kg) administered via a 40-minute infusion elicited robust antidepressant effects within hours of administration that lasted for several days.

However, it was a follow-up study of 17 treatment-resistant patients with MDD by Zarate and colleagues9 that truly ignited interest in the NMDA receptor as a viable target for antidepressant drug development. This placebo-controlled, randomized, crossover study found 71% of the participants to have a greater than 50% reduction in depressive symptoms within 24 hours of ketamine administration, while the same participants showed almost no change in symptoms following the placebo saline injection. Moreover, the response was sustained for the 1-week follow-up in approximately one-third of the participants. There have been 3 additional placebo-controlled crossover studies that showed very similar findings of rapid onset of robust antidepressant activity lasting for several days to weeks after a single subanesthetic dose of ketamine in the treatment of major depressive episodes associated with both MDD and bipolar disorder.10-12

Numerous open-label studies and case series provide additional evidence of ketamine’s antidepressant effect and further characterize its effects in unique patient populations. Rapid reductions in suicidal ideation in depressed patients who received ketamine have been reported.13,14 Other studies have begun to examine the potential benefits of adding ketamine to the anesthetic regimen of patients undergoing ECT. While some early reports suggest benefits, the proper use of the drug in this situation may need to be more clearly detemined.15,16 Still other reports have begun to evaluate the potential use of ketamine in palliative care settings, where the drug’s pain-reducing effects may provide an additional benefit.17,18